The invention relates to a stereospecific method for the preparation of 2(S),4(S),5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryloctanoyl amides and their physiologically acceptable salts; and new compounds used as intermediates in the multistage process.
In EP-A-0 678 503, xcex4-amino-xcex3-hydroxy-xcfx89-aryl-alkanecarbox-amides are described, which exhibit renin-inhibiting properties and could be used as antihypertensive agents in pharmaceutical preparations. The manufacturing procedures described are unsatisfactory in terms of the number of process steps and yields and are not suitable for an industrial process. A disadvantage of these processes is also that the total yields of pure diastereomers that are obtainable are too small.
It has now been surprisingly found that these alkanecarboxamides can be prepared both in high total yields and in a high degree of purity, and that selectively pure diastereomers are obtainable, if the double bond of 2,7-dialkyl-8-aryl-4-octenic acid amides is simultaneously halogenated in the 5 position and hydroxylated in the 4 position under lactonization, the lactone ring is opened with an amine during the formation of the carboxamide, then the hydroxy group is replaced with azide, if necessary after protection of the hydroxy group, the resulting compound is lactonized, the lactone amidated and then the azide group converted to the amine group.
A first object of the invention is a process for the preparation of compounds of formula I and their physiologically acceptable salts, 
wherein
R1 and R2 are, independently of one another, H, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, or C1-C6alkoxy-C1-C6alkyloxy, R3 is C1-C6alkyl, R4 is C1-C6alkyl, and R5 is C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy-C1-C6-alkyl, C1-C6alkanoyloxy-C1-C6alkyl, C1-C6aminoalkyl, C1-C6alkylamino-C1-C6-alkyl, C1-C6-dialkylamino-C1-C6-alkyl, C1-C6-alkanoyl-amido-C1-C6-alkyl, HO(O)Cxe2x80x94C1-C6-alkyl, C1-C6alkyl-Oxe2x80x94(O)Cxe2x80x94C1-C6alkyl, H2Nxe2x80x94C(O)xe2x80x94C1-C6alkyl, C1-C6alkyl-HNxe2x80x94C(O)Cxe2x80x94C6alkyl or (C1-C6alkyl)2Nxe2x80x94C(O)xe2x80x94C1-C6-alkyl, comprising the steps
a) reaction of a compound of formula II, 
with an amine of formula R5xe2x80x94NH2 to form a compound of formula III, 
and
b) reduction of the azide group of the compound of formula III to the amine group and isolation of the compounds of formula I, if necessary with the addition of a salt-forming acid, comprising the preparation of the compound of formula II by reacting
c) a compound of formula IV 
wherein X is Cl, Br or I, with an amine to form a carboxamide of formula V, 
wherein R6 is an amino group,
d1) azidating a compound of formula V to form a compound of formula VI 
d2) protecting the hydroxyl group in the compounds of formula V, and azidating the resulting compound of formula VII 
wherein S is a protecting group, to form a compound of formula VIII, 
e) and then lactonizing the compound of formula VI or VIII in the presence of an acid to form a compound of formula II.
As an alkyl, R1 and R2 may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl.
As a halogenalkyl, R1 and R2 may be linear or branched and preferably comprise 1 to 4 C atoms, especially 1 or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloro-methyl, 2-chloroethyl and 2,2,2-trifluoroethyl.
As an alkoxy, R1 and R2 may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methoxy, ethoxy, n- and i-propyloxy, n-, i- and t-butyloxy, pentyloxy and hexyloxy.
As an alkoxyalkyl, R1 and R2 may be linear or branched. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyl group preferably comprises 1 to 4 C atoms. Examples are methoxymethyl, 1-methoxyeth-2-yl, 1-methoxyprop-3-yl, 1-methoxybut-4-yl, methoxypentyl, methoxyhexyl, ethoxymethyl, 1-ethoxyeth-2-yl, 1-ethoxyprop-3-yl, 1-ethoxybut-4-yl, ethoxypentyl, ethoxyhexyl, propyloxymethyl, butyloxymethyl, 1-propyloxyeth-2-yl and 1-butyloxyeth-2-yl.
As a C2-C6alkoxy-C1-C6alkyloxy, R1 and R2 may be linear or branched. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyloxy group preferably comprises 1 to 4 C atoms. Examples are methoxymethyloxy, 1-methoxyeth-2-yloxy, 1-methoxyprop-3-yloxy, 1-methoxybut-4-yloxy, methoxypentyloxy, methoxyhexyloxy, ethoxymethyloxy, 1-ethoxyeth-2-yloxy, 1-ethoxyprop-3-yloxy, 1-ethoxybut-4-yloxy, ethoxypentyloxy, ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 1-propyloxyeth-2-yloxy and 1-butyloxyeth-2-yloxy.
In a preferred embodiment, R1 is methoxy- or ethoxy-C1-C4alkyloxy, and R2 is preferably methoxy or ethoxy. Particularly preferred are compounds of formula I, wherein R1 is 1-methoxyprop-3-yloxy and R2 is methoxy.
As an alkyl, R3 and R4 may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl. In a preferred embodiment, R3 and R4 in compounds of formula I are in each case isopropyl.
As an alkyl, R5 may be linear or branched and preferably comprise 1 to 4 C atoms. Examples of alkyl are listed hereinabove. Methyl, ethyl, n- and i-propyl, n-, i- and t-butyl are preferred.
As a C1-C6hydroxyalkyl, R5 may be linear or branched and preferably comprise 2 to 6 C atoms. Some examples are 2-hydroxyethy-1-yl, 2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl, 2-, 3- or 4-hydroxybut-1-yl, hydroxypentyl and hydroxyhexyl.
As a C1-C6alkoxy-C1-C6alkyl, R5 may be linear or branched. The alkoxy group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are 2-methoxyethy-1-yl, 2-methoxyprop-1-yl, 3-methoxyprop-1-yl, 2-, 3- or 4-methoxybut-1-yl, 2-ethoxyethy-1-yl, 2-ethoxy-prop-1-yl, 3-ethoxyprop-1-yl, and 2-, 3- or 4-ethoxybut-1-yl.
As a C1-C6alkanoyloxy-C1-C6alkyl, R5 may be linear or branched. The alkanoyloxy group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are formyloxymethyl, formyloxyethyl, acetyloxy-ethyl, propionyloxyethyl and butyroyloxyethyl.
As a C1-C6aminoalkyl, R5 may be linear or branched and preferably comprise 2 to 4 C atoms. Some examples are 2-aminoethyl, 2- or 3-aminoprop-1-yl and 2-, 3- or 4-aminobut-1-yl.
As a C1-C6alkylamino-C1-C6alkyl and C1-C6dialkylamino-C1-C6-alkyl, R5 may be linear or branched. The alkylamino group preferably comprises C1-C4alkyl groups and the alkyl group preferably 2 to 4 C atoms. Some examples are 2-methylaminoeth-1-yl, 2-dimethylaminoeth-1-yl, 2-ethylamino-eth-1-yl, 2-ethylaminoeth-1-yl, 3-methylaminoprop-1-yl, 3-dimethylaminoprop-1-yl, 4-methylaminobut-1-yl and 4-dimethylaminobut-1-yl.
As a C1-C6alkanoylamido-C1-C6alkyl, R5 may be linear or branched. The alkanoyl group preferably comprises 1 to 4 C atoms and the alkyl group preferably 1 to 4 C atoms. Some examples are 2-formamidoeth-1-yl, 2-acetamidoeth-1-yl, 3-propionylamidoeth-1-yl and 4-butyroylamidoeth-l-yl.
As a HO(O)Cxe2x80x94C1-C6-alkyl, R5 may be linear or branched, and the alkyl group preferably comprises 2 to 4 C atoms. Some examples are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.
As a C1-C6-alkyl-Oxe2x80x94(O)Cxe2x80x94C1-C6alkyl, R5 may be linear or branched, and the alkyl groups preferably comprise independently of one another 1 to 4 C atoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonyleth-1-yl, 3-methoxycarbonylprop-1-yl, 4-methoxycarbonylbut-1-yl, ethoxy-carbonylmethyl, 2-ethoxycarbonyleth-1-yl, 3-ethoxycarbonyl-prop-1-yl, and 4-ethoxycarbonylbut-1-yl.
As a H2Nxe2x80x94C(O)xe2x80x94C1-C6alkyl, R5 may be linear or branched, and the alkyl group preferably comprises 2 to 6 C atoms. Some examples are carbamidomethyl, 2-carbamidoeth-1-yl, 2-carbamido-2,2-dimethyleth-1-yl, 2- or 3-carbamidoprop-1-yl, 2-, 3- or 4-carbamidobut-1-yl, 3-carbamido-2-methylprop-1-yl, 3-carbamido-1,2-dimethylprop-1-yl, 3-carbamido-3-methyl-prop-1-yl, 3-dicarbamido-2,2-dimethylprop-1-yl, 2-, 3-, 4- or 5-carbamidopent-1-yl, 4-carbamido-3, 3- or -2,2-di-methylbut-1-yl.
As a C1-C6alkyl-HNxe2x80x94C(O)xe2x80x94C1-C6-alkyl or (C1-C6alkyl)2Nxe2x80x94C(O)xe2x80x94C1-C6-alkyl, R5 may be linear or branched, and the NH-alkyl group preferably -comprises 1 to 4 C atoms and the alkyl group preferably 2 to 6 C atoms. Examples are the carbamidoalkyl groups defined hereinabove, whose N atom is substituted with one or two methyl, ethyl, propyl or butyl.
A preferred subgroup of compounds of formula I is that in which R1 is C1-C4alkoxy or C1-C4alkoxy-C1-C4alkyloxy, R2 is C1-C4alkoxy, R3 is C1-C4alkyl, R4 is C1-C4alkyl and R5 is H2NC(O)xe2x80x94C1-C6alkyl which if necessary is N-monosubstituted or N-di-C1-C4alkyl substituted.
A more preferred subgroup of compounds of formula I is that in which R1 is methoxy-C2-C4-alkyloxy, R2 is methoxy or ethoxy, R3 is C2-C4alkyl, R4 is C2-C4alkyl and R5 is H2NC(O)xe2x80x94C1-C6alkyl.
An especially preferred compound of formula I is that in which R1 is 3-methoxy-prop-3-yloxy, R2 is methoxy, R3 and R4 are 1-methyleth-1-yl, and R5 is H2NC(O)-[C(CH3)2]xe2x80x94CH2xe2x80x94.
As an amino group, R6 may be xe2x80x94NH2, primary and preferably secondary amino, the amino groups comprising 1 to 20 C atoms and preferably 2 to 12. The amino group preferably corresponds to the formula xe2x80x94N(R7)2, wherein R7 is C1-C4alkyl, cyclopentyl, cyclohexyl, phenyl or benzyl, or both R7 are together tetramethylene, pentamethylene or 3-oxapentylene. Preferred examples of R7 are methyl, ethyl, n-propyl and n-butyl.
Protecting group S in the compounds of formulae VII and VIII are preferably acyl groups, which may comprise 1 to 12 and preferably 1 to 8 C atoms. Some examples are formyl, acetyl, propionyl and butyroyl. Acetyl is especially preferred.
The individual process steps may be carried out in the presence of solvent. Suitable solvents are water and organic solvents, especially polar organic solvents, which can also be used as mixtures of at least two solvents. Examples of solvents are hydrocarbons (petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene, xylene), halogenated hydrocarbon (dichloromethane, chloroform, tetrachloroethane, chlorobenzene); ether (diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl or diethyl ether); carbonic esters and lactones (methyl acetate, ethyl acetate, methyl propionate, valerolactone); N,N-substituted carboxamides and lactams (dimethylformamide, dimethylacetamide, N-methylpyrrolidone); ketones (acetone, methylisobutylketone, cyclohexanone); sulfoxides and sulfones (dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone); alcohols (methanol, ethanol, n- or i-propanol, n-, i- or t-butanol, pentanol, hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl or dihydroxy-methyl cyclohexane, benzyl alcohol, ethylene glycol, diethylene glycol, propanediol, butanediol, ethylene glycol monomethyl or monoethyl ether, and diethylene glycol monomethyl or monoethyl ether; nitriles (acetonitrile, propionitrile); tertiary amines (trimethylamine, triethyl-amine, tripropylamine and tributylamine, pyridine, N-methyl-pyrrolidine, N-methylpiperazine, N-methylmorpholine) and organic acids (acetic acid, formic acid).
Process Step a)
The reaction of compounds of formula II with a compound R5NH2 by opening of the lactone ring to form compounds of formula III is expediently carried out in the presence of alcohols or amines which are capable of forming activated carbonic esters or carboxamides. Such compounds are well-known. They may be 2-hydroxypyridine, N-hydroxycarboxamides and imides, and carboximides (N-hydroxysuccinimide). Organic solvents are used as solvent, tertiary amines being of advantage, for example trimethylamine or triethylamine. The reaction temperature may range for example from approximately 40xc2x0 C. to 150xc2x0 C. and preferably from 50xc2x0 C. to 120xc2x0 C.
Process Step b)
Reduction of the azide group to the amine group in the compounds of formula III takes place in a manner known per se (see Chemical Reviews, Vol. 88 (1988), pages 298 to 317), for example using metal hydrides or more expediently using a catalytic method with hydrogen in the presence of homogeneous (Wilkinson catalyst) or heterogeneous catalysts, for example Raney nickel or precious metal catalysts such as platinum or palladium, if necessary on substrates such as carbon. The hydrogenation can also be carried out if necessary catalytically under phase transfer conditions, for example with ammonium formate as hydrogen donor. It is of advantage to use organic solvents. The reaction temperature may range for example from approximately 0xc2x0 C. to 200xc2x0 C. and preferably from 10xc2x0 C. to 100xc2x0 C. Hydrogenation may be carried out at normal pressure or increased pressure up to 100 bar, for example, and preferably up to 50 bar.
The compounds of formula I may be converted to addition salts in a manner known per se by treatment with monobasic or polybasic, inorganic or organic acids. Hemifumarates are preferred.
Process Step c)
The reaction of the halolactone with an amine to form carboxamide is advantageously carried out in organic solvents such as halogenated hydrocarbons (chloroform, dichloromethane). The reaction temperature may range for example from approximately xe2x88x9230xc2x0 C. to 80xc2x0 C. and preferably from xe2x88x9220xc2x0 C. to 50xc2x0 C. The amine is expediently used as a salt, for example as a halogenide. Dimethyl ammonium chloride is preferably used. The reaction is preferably carried out in the presence of at least equimolar quantities of an alkyl aluminium halogenide such as dialkyl aluminium chloride (dimethyl or diethyl aluminium chloride). After hydrolytic treatment, the carboxamide can be isolated by means of extraction and purified by means of chromatography. The stereoselectivity is high and the yield can be as much as 70% or more.
Process Step d1)
Halogen X may be directly substituted with azide in the carboxamide of formula V obtained as described in step c). Suitable azidation agents are for example metal azides, especially alkaline earth metal azides and alkali metal azides, as well as silyl azides. Especially preferred azidation agents are lithium azide, sodium azide and potassium azide. The reaction may be carried out in organic solvents, for example N-alkylated lactams such as N-methylpyrrolidone or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU). The reaction temperature may range for example from approximately 20xc2x0 C. to 150xc2x0 C. and preferably from 20xc2x0 C. to 120xc2x0 C. It may be expedient to include the use of phase; transfer catalysts. In the broader sense it is advantageous to carry out the reaction in the presence of preferably at least equimolar quantities of a base, especially tertiary amines. These tertiary amines may serve at the same time as solvents. The preparation and synthetic use of azides are described for example by E. F. V. Scriven in Chemical Reviews, Vol. 88 (1988), pages 298 to 317. As a result of secondary reactions due to the absence of the hydroxyl group, the yield in the non-optimized reaction is not very high and may be about 30% or more.
Process Step d2)
It has therefore proved very advantageous to protect the hydroxyl group against azidation in the compounds of formula VI, preferably with acyl groups. To this end, compounds of formula V are reacted with acylation agents, for example carboxylic acid anhydrides such as acetic acid anhydride or carboxylic acid halogenides such as acetylchloride. The reaction may be carried out with or without solvents. The reaction temperature may be xe2x88x9220 to 80xc2x0 C. The reaction is expediently carried out in the presence of bases, for example tertiary amines. Examples of tertiary amines are trialkylamines (trimethylamine, triethylamine), N-alkylated cyclic amines (N-alkylpyrrolidine), dialkylaminopyridines (dimethylaminopyridine) and pyridine. After hydrolytic treatment, the protected carboxamide can be isolated by means of extraction and purified by means of chromatography. The yield is generally more than 90%.
Azidation may then be carried out as described in process step d1). The yields are substantially higher than with direct azidation as described in process step d1) and are more than 75% in the non-optimized process step d2)
Process Step e)
Lactonization of compounds of formula VI or VIII to form compounds of formula II is expediently carried out at a temperature of xe2x88x9220 to 100xc2x0 C. and in the presence of a solvent such as alcohols (methanol, ethanol or propanol) or hydrocarbons (benzene, toluene or xylene). Inorganic acids and advantageously organic acids are used, especially mineral acids such as hydrochloric acid, hydrobromic acid or sulfuric acid, sulfonic acids and carboxylic acids. The azidolactone of formula II may be isolated for example by extraction with organic solvents. The desired stereoisomer is also formed in this step at high yields of up to 90% or more.
Some intermediates prepared using the process according to the invention are new and represent further objects of the invention.
A further object of the invention is thus a compound of formula IX, 
wherein
X is halogen, R1 and R2 are, independently of one another, H, C1-C6alkyl, C1-C6-halogenalkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, or C1-C6alkoxy-C1-C6alkyloxy, R3 is C1-C6alkyl, R4 is C1-C6alkyl, R6 is an amino group, and R8 is a protecting group or hydrogen.
A further object of the invention is a compound of formula IXa, 
wherein
R1 and R2 are, independently of one another, H, C2-C6alkyl, C1-C6-halogenalkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, or C1-C6alkoxy-C1-C6alkyloxy, R3 is C1-C6alkyl, R4 is C1-C6alkyl, R6 is an amino group, and R8 is a protecting group or hydrogen.
For residues X, R1, R2, R3, R4, R6, and R8 in compounds of formulae IX and IXa, the embodiments and preferences described hereinbefore apply.
The compounds of formula IV are obtainable by reacting in a first step a compound of formula X, 
with a compound of formula IX, 
wherein R1 to R4 are as defined hereinbefore, including the preferences, Y is Cl, Br or I and Z is Cl, Br or I (Y and Z are preferably Br and especially Cl), and R9 is C1-C6alkyl, R10 is C1-C6-akyl or C1-C6alkoxy, or R9 and R10 are together tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or xe2x80x94CH2CH2Oxe2x80x94C(O)xe2x80x94 substituted if necessary with C1-C4alkyl, phenyl or benzyl, in the presence of an alkali or alkaline earth metal to form a compound of formula XII, 
wherein
R9 is C1-C6alkyl, R10 is C1-C6alkyl or C1-C6alkoxy, or R9 and R10 together are tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or xe2x80x94CH2CH2Oxe2x80x94C(O)xe2x80x94 substituted if necessary with C1-C4alkyl, phenyl or benzyl.
As an alkyl, R9 and R10 in formula XII may be branched and preferably linear and are preferably C1-C4alkyl, for example methyl or ethyl. R10 as alkoxy may preferably be linear and is preferably C1-C4alkoxy, for example methoxy or ethoxy. R9 and R10 together are preferably tetramethylene, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94 or xe2x80x94CH(CH2C6H5) CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94.
The coupling of Grignard reagents with alkenyl halogenides in an ether such as, for example, tetrahydrofuran or dioxan as solvents in the presence of catalytic quantities of a soluble metal complex, for example an iron complex such as iron acetonyl acetate, and in the presence of more than equimolar quantities of a solvent stabilizing the metal complex, for example n-methylpyrrolidone, is described by G. Cahiez et al. in Synthesis (1998), pages 1199-1200. The reaction temperature may for example be xe2x88x9250 to 80xc2x0 C., preferably xe2x88x9220 to 50xc2x0 C. Catalytic quantities may for example be 0.1 to 20% by weight in relation to a compound of formula VII. It is expedient to carry out the reaction so that initially a compound of formula VI is converted to a Grignard compound (for example with magnesium) and then adding a solution of a compound of formula VII, metal complex and N-methylpyrrolidone, or vice versa.
It was found to be of advantage when only catalytic quantities of a solvent stabilizing the metal complexes, for example n-methylpyrrolidone, were used. Catalytic quantities may for example be 1 to 10 mol percent, preferably 1 to 5 mol percent, in relation to the compounds of formula XI or XII.
Compounds of formula X in the form of their racemates or enantiomers are known or capable of being prepared according to analogous Processes. For example, R1R2phenylaldehyde may be reacted with R3diethoxyphosphorylacetic acid ester to form 2-R3-3-(R1R2phenyl)acrylic acid esters, these may then be hydrogenated to form the corresponding propionic acid esters, the ester group saponified and the carboxylic acid reduced to alcohol, and finally the hydroxyl group substituted with halogen. Enantiomers are obtainable by separating the racemates of the carboxylic acids with for example quinine or by enzymatic resolution of the racemates of the corresponding carboxylic acid esters. Details are described in the examples. A possible asymmetric synthesis of compounds of formula VI is described in EP-A-0 678 503.
Compounds of formula XI in the form of their racemates or enantiomers may be prepared by the reaction of metalled carbonic esters of formula R4CH2COOR (for example lithium isovaleric acid esters) with trans-1,3-halogenpropene, then halogenation of the resulting carboxylic acid to form the acid halogenide and reaction with a secondary amine. The coupling of metalled carbonic esters with trans-1,3-halogenpropene can be carried out asymmetrically according to the method described by D. A. Evans in Asymmetric Synthesis, Vol. 3, 1984 (Academic Press Inc.), pages 2-110. Enantiomers are obtainable by separating the racemates of the carboxylic acids with for example cinchonidine or by enzymatic separation of the racemates of the corresponding carbonic esters.
In a second process step, compounds of formula XII are reacted with a halogenation agent in the presence of water and if necessary an acid to form a compound of formula IV.
Suitable chlorination, bromination and iodination agents are elemental bromine and iodine, in particular N-chloro, N-bromo and N-iodocarboxamides and dicarboximides. Preferred are N-chloro, N-bromo and N-iodophthalimide and especially chloro, N-bromo and N-iodosuccinimide, as well as tertiary butyl hypochlorite and N-halogenated sulfonamides and sulfonimides, for example chloramine T. It is of advantage to carry out the reaction in organic solvents. The reaction temperature may range for example from approximately xe2x88x9270xc2x0 C. to ambient temperature and preferably from xe2x88x9230xc2x0 C. to 10xc2x0 C. Carboxamides are advantageously lactonized in the presence of inorganic or organic acids, at least equimolar quantities of water, and reacted in the presence of water-miscible solvents, for example tetrahydrofuran or dioxane. Suitable acids are for example formic acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, trifluoro-methanesulfonic acid, toluenesulfonic acid, H2SO4, H3PO4, hydrogen halides, acid ion exchange resins, and acids immobilized on solid carriers. Water is generally used in at least equimolar quantities.
With the choice of lactones of formula IV, the compounds of formula I, which per se are complex compounds, can be prepared in a convergent and simple manner, which is especially true of these enantioselective or diastereo-selective synthesis. The total yield from all process steps a) to e) may amount to 40% or more, which makes an industrial application feasible.